Lenalidomide (LEN) and its analogue, pomalidomide, promote erythroid lineage competence and in vitro colony-forming capacity. The best results with LEN are obtained in patients with deletion 5q. In patients with non-del(5q) MDS, LEN restores erythropoiesis in only a subset of patients (List, et al. N. Eng. J. Med. 352:549 (2005)). Such responders to LEN treatment display repression of erythroid-specific genes and that LEN restored transcriptional response to erythropoietin (Epo) (Ebert, et al. PLoS Medicine 5(2):e35 (2008)). This could suggest that LEN enhances Epo receptor (R) signal fidelity. LEN induces cellular expression of JAK2-associated EpoR in a concentration-dependent manner (Basiorka, et al. Blood. 118: 2382a (2011)). However, the mechanism of this regulation was unclear.
The cereblon RING (really interesting new gene) finger domain containing E3-ubiquitin ligase complex has been implicated as a key target of the immunomodulatory drugs (IMiDs) responsible for the teratogenic effects of thalidomide and the cytotoxic effects of LEN in multiple myeloma (Ito et al. Science. 327:1345-50 (2010); Zhu, et al. Blood. 118:4771-4779 (2011)). LEN interacts with the RING finger E3 ubiquitin ligase, murine double minute 2 (MDM2) to inhibit ligase ubiquitination, and stabilize the protein (Wei et al. Oncogene, MS#ONC-2011-01840R (2012)).
However, biomarkers are still needed that predict responsiveness to LEN in subjects with non-del(5q) MDS. Moreover, additional therapeutics are needed to treat subjects with non-del(5q) MDS, especially those that are not responders to LEN treatment.